Vasodilatory terpeno-phenoxyalkylamines

ABSTRACT

New terpeno-phenoxyalkylamines of the general formula: ##STR1## in which n is 0, 1 or 2, R 1  is a hydrogen atom, a lower alkyl radical having a straight or branched chain with 1 to 4 carbon atoms, or an OH group, 
     R 2  and R 3  each represent H, or a lower alkyl radical having a straight chain or branched chain with up to 4 carbon atoms, or a hydroxyethyl radical, 
     R 4  is a terpene radical selected from 2-isobornyl, 5-camphyl or 2-norbornyl of exo or endo configuration in the ortho, meta or para position with respect of the ether function 
     R 5  and R 6  may each be H, a lower alkyl radical having a straight or branched chain with up to 4 carbon atoms or a halogen atom, 
     As well as their physiologically acceptable non-toxic acid salts and their quaternary ammonium salts having antibacterial and cardiovascular vasodilatory properties.

The present invention relates to new terpeno-phenoxyalkylamines of thegeneral formula: ##STR2## in which n = 0,1 or 2;

R₁ may be H, or a lower alkyl radical having a straight or branchedchain with up to 4 carbon atoms, or an OH group,

R₂ and R₃ each represent H or a lower alkyl radical having a straight orbranched chain with up to 4 carbon atoms, or a hydroxyethyl radical,

R₄ is a terpene radical: 2-isobornyl (a), or 5-camphyl (b), or2-norbornyl (c), ##STR3## OF EXO OR ENDO CONFIGURATION, IN THE ORTHO,META OR PARA POSITION WITH RESPECT TO THE ETHER FUNCTION;

R₅ and R₆ may each be H or a lower alkyl radical having up to 4 carbonatoms, saturated or unsaturated having a straight or branched chain, ora halogen atom: Cl, Br, I, F.

More particularly:

R₁ is H, or OH

n is equal to zero or 1

R₂ is a hydrogen atom,

R₃ is a hydrogen atom or isopropyl radical or a hydroxyethyl group --CH₂ CH₂ --OH

R₅, R₆ each represent a hydrogen atom or a halogen atom, in particularCl, or Br, or a methyl radical, in position 4 or 5 of the phenol ring.

These amino ethers possess, in particular, interesting bacteriostaticand bactericidal properties vis-a-vis Gram + and Gram - bacteria and maybe used as anti-infectous agents. They also have vasodilatory andcardiovascular properties. They may be used in the form of bases orsalts of physiologically acceptable non-toxic acids or as quaternaryammonium salts.

Advantageously, it is possible to prepare the terpenophenoxyalkylaminesaccording to the invention of formula I in which R₁ is an OH group and nis equal to 1, by the action of an alkali metal terpenophenate offormula: ##STR4## in which M designates an alkaline metal, in particularsodium and R₄, R₅, R₆ are defined as above, the epichlorohydrin to formthe corresponding 1-terpenophenoxy-2,3-epoxypropane ##STR5## which isreacted with ammonia in an alcoholic solution or an amine HNR₂ R₃ toobtain the desired terpenophenoxy-alkylamine.

It is possible to prepare terpeno-phenoxyalkylamines of formula I inwhich R₁, R₂, R₃ are hydrogen atoms, n is equal to zero, by condensationof an alkaline terpenophenate of formula: ##STR6## in which M designatesan alkaline metal and R₄, R₅, R₆ are defined as above with thechloroacetonitrile to form the corresponding 2-terpenophenoxyacetonitrile, derivative followed by the reduction of the nitrilefunction to an amine by diborane or another appropriate reducing agent.

It is possible to prepare terpeno-phenoxyalkylamines of formula I, inwhich R₁ and R₂ are hydrogen atoms and R₃ is a hydroxyethyl group, byreduction of the corresponding amide. ##STR7## in particular by means ofa metallic hydride, for example lithium and aluminium hydride.

The following examples are given to illustrate the invention, withoutlimiting the scope thereof.

EXAMPLE 1

2-(2'-isobornyl-4',5'-dimethylphenoxy) ethylamine.

In a 100 cm³ flask fitted with a condenser and a nitrogen feed pipethere is introduced 2.5g (0.01 mole) of 2-isobornyl-4,5-dimethylphenol,20 cm³ of methylethyl ketone and 1.38g (0.01 mole) of anhydrouspotassium carbonate. The reaction mixture is refluxed for 3 hours aftervigorous stirring, and then 24 cm³ of a 0.5N solution ofchloroacetonitrile in methylethyl ketone containing 1g of potassiumiodide are added dropwise. After 22 hours reflux, the mixture isfiltered and the solvent evaporated under reduced pressure. The residueis extracted with chloroform, the organic phase washed with water, driedand the solvent evaporated. The residue is taken up with pentane thencrystallised in ethanol. 1.5g of 2-(2'-isobornyl-4',5'-dimethylphenoxy)acetonitrile are obtained, which is dissolved in 100 ml oftetrahydrofuran and treated for 1 hour with a stream of diborane. After24 hours of contact the excess reagent is destroyed with caution, byethanol and the solvent is removed. The residue is taken up withhydrochloric ether (a solution of hydrochloric acid in ether) thenwashed with anhydrous ether. By crystallisation in acetone there isobtained 1.2g of pure product as the hydrochloride (m.pt. 174°-176° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.20 H.sub.32 Cl NO (M.W. = 337.5)                                      C      H        N        Cl                                        ______________________________________                                        Calculated (%)                                                                             71.1     9.48     4.15   10.5                                    Found (%)    70.9     9.6      4.1    10.3                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed.

    ______________________________________                                        Isobornyl   2880,       2950 cm.sup.-1                                        Aromatic nucleus                                                                          1500, 845                                                         Combined ether                                                                            1255,       1100, 1020                                            --NH.sub.3 .sup.+                                                                         3000,       2500, 2000, 1610, 1510                                ______________________________________                                    

N.M.R. SPECTRA

In deuterated dimethylsulfoxide, with a T.M.S. reference, the followingpeaks are noted.

    ______________________________________                                        CH.sub.3                                                                              bridge head 0.6 ppm        Singlet                                    CH.sub.3                                                                              geminal     0.75-0.77 ppm  Singlets                                   CH.sub.2                                                                              cyclic      1.6 ppm        massive                                    CH.sub.2                                                                              ethylamino  3.15 and 4.15 ppm                                         --NH.sub.3.sup.+    7.05 ppm       Singlet                                    ______________________________________                                    

EXAMPLE 2

2-(2'-isobornyl-4'-bromo-5'-methylphenoxy) ethylamine

In a 250 cm³ flask provided with a nitrogen delivery tube, there isintroduced 15.6g (0.048 mole) of 2-isobornyl-4-bromo-5-methylphenol, 90cm³ of methylethyl ketone and 6.6g (0.048 mole) of anhydrous potassiumcarbonate. The reaction mixture is heated at reflux for 3 hours withvigorous magnetic stirring then there is added dropwise a 0.5N solutionof chloroacetonitrile in methylethyl ketone containing 1g of potassiumiodide. After 22 hours reflux the mixture is filtered on a basic aluminacolumn then eluted with 400 cm³ of ether. After evaporation of thesolvent, the residue is crystallised in ethanol and there is thusobtained 14.5g of 2-isobornyl-4-bromo-5-methylphenoxy acetonitrile.

A solution of 5g of the preceding product in 50 cm³ of tetrahydrofuranmaintained at ambient temperature is treated for 1 hour with a stream ofdiborane then left for 18 hours. The mixture is then treated, withcaution, with 5 cm³ of ethanol, the solvent evaporated and the residuetaken up with hydrochloric ether. There is thus obtained 4.5g of pureproduct in the form of the hydrochloride (m. pt. = 222°-224° C)

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.19 H.sub.29 NO Cl Br (M.W. = 402.3)                                   C     H       N       Cl    Br                                     ______________________________________                                        Calculated (%)                                                                             56.67   7.2     3.48  8.81  19.86                                Found (%)    56.4    7.0     3.6   8.7   20.1                                 ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed.

    ______________________________________                                        Isobornyl        2880, 2950 cm.sup.-1                                         brominated                                                                    aromatic nucleus 1500, 845                                                    combined ether   1250, 1160, 1040                                             --NH.sub.3.sup.+ 3000, 2500, 2000, 1610, 1490                                 ______________________________________                                    

N.M.R. SPECTRA

In deuterated chloroform with a T.M.S. reference, the following peaksare observed:

    ______________________________________                                        CH.sub.3                                                                              bridge head 0.6 ppm        Singlet                                    CH.sub.3                                                                              geminal     0.78 and 0.80 ppm                                                                            Singlets                                   CH.sub.3                                                                              aromatic    2.3 ppm        Singlet                                    CH.sub.2                                                                              cyclic      1.6 ppm        massive                                    CH.sub.2                                                                              ethaylamino 3.3 and 4.15 ppm                                          --NH.sub.3.sup.+    7.35 ppm       Singlet                                    ______________________________________                                    

EXAMPLE 3

2-(2'-isobornyl-4'-bromophenoxy) ethylamine

In a 500 cm³ flask fitted with a condenser and a nitrogen delivery tube,there is introduced 19g (0.06 mole) of 2-isobornyl-4-bromophenol, 150cm³ of methylethyl ketone and 12.5g (0.09 mole) of anhydrous potassiumcarbonate. The mixture is raised to reflux for 3 hours, under vigorousstirring, and then 150 cm³ of a 0.5N solution of chloroacetonitrile inmethylethyl ketone containing 1g of potassium iodide are added dropwise.After 22 hours reflux, the mixture is filtered on an alumina column andeluted with 200 cm³ of ether. After evaporation of the solvent, an oilis obtained which, by crystallisation in pentane, gives 19g of2-isobornyl-4-bromophenoxy acetonitrile. A solution of 18.5g of thepreceding product in 200 cm³ of tetrahydrofuran is treated for 1 hour atambient temperature with a current of diborane. The mixture is left for18 hours and treated, with caution, with 20 cm³ of ethanol and thenconcentrated under reduced pressure. The residue is taken up with a 20%solution of hydrochloric acid in ether. After extraction with ether andalkalization there is isolated 14.5g of a product which is transformedto the hydrochloride by hydrochloric ethanol and separated byprecipitation with ether. There is thus obtained 13g of pure product(m.pt. 239°-240° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.18 H.sub.27 NO Br Cl (M.W. = 388.35)                                  C     H       N       Cl    Br                                     ______________________________________                                        Calculated % 55.6    6.95    3.61  9.13  20.57                                Found %      55.3    7.05    3.5   9.2   20.4                                 ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed:

    ______________________________________                                        Isobornyl        2880, 2950 cm.sup. -1                                        Aromatic nucleus 1490, 890, 810                                               combined ether   1240, 1040                                                   --NH.sub.3.sup.+ 3000, 2500, 2000, 1600, 1500                                 ______________________________________                                    

N.M.R. SPECTRA

In deuterated dimethyl sulfoxide, with a T.M.S. reference, the followingpeaks are noted:

    ______________________________________                                        CH.sub.3                                                                              bridge head 0.6 ppm        Singlet                                    CH.sub.3                                                                              geminal     0.78 and 0.80 ppm                                                                            Singlets                                   CH.sub.2                                                                              cyclic      1.62 ppm                                                  CH.sub.2                                                                              ethylamino  3.2 and 4.2 ppm                                           --NH.sub.3.sup.+    8.55 ppm                                                  ______________________________________                                    

EXAMPLE 4

3-(2'-isobornyl-4,5'-dimethylphenoxy)-1-amino propan-2-ol

258g (1 mole) of 2-isobornyl-4,5-dimethylphenol are dissolved in 300 cm³toluene and 23g sodium are added. The mixture is heated to reflux untilhydrogen is no longer evolved and the solvent is then evaporated. Thephenate formed is dissolved in 300 cm³ of tetrahydrofuran and 185g (2moles) of epichlorohydrin are added dropwise and the mixture refluxedfor 18 hours. The solvent is evaporated, the residue taken up in ether,the sodium chloride formed is separated and the ether removed. Theimpure residue is purified on a silica column by elution with a 1:1benzene: cyclohexane mixture. There is thus obtained, as an oil, 255g of1-(2'-isobornyl-4,5'-dimethylphenoxy)-2,3-epoxy propane. 33.1g (0.1mole) of the preceding product are dissolved in a solution of 34gammonia in 500 cm³ ethanol. After 3 hours of contact, the mixture isevaporated to dryness under reduced pressure and the residual oildissolved in ether. The ethereal phase is washed with water toneutrality, dried over magnesium sulphate and the ether removed undervacuum. The residue is dissolved in hydrochloric ethanol and thehydrochloride formed is precipitated with ether and crystallised inacetone. There is thus obtained a pure product (m.pt. 280°-282° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.21 H.sub.34 NO.sub.2 Cl (M.W. = 367.9)                                C      H        N        Cl                                        ______________________________________                                        Calculated (%)                                                                             68.55    9.33     3.81   9.64                                    Found (%)    68.3     9.1      3.9    9.5                                     ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed:

    ______________________________________                                        Isobornyl        2880 2950 cm.sup. -1                                         Aromatic nucleus 1620, 1510, 850                                              Combined ether   1260, 1035                                                   --NH.sub.3.sup.+ 3000, 2000, 1600, 1510                                       OH               3400, 1105                                                   ______________________________________                                    

N.M.R. SPECTRA

In deuterated dimethylsulfoxide, with a T.M.S. reference the followingpeaks are observed.

    ______________________________________                                        CH.sub.3                                                                              bridge head 0.55 ppm       Singlet                                    CH.sub.3                                                                              geminal     0.75 ppm       doublet                                    CH.sub.3                                                                              aromatic    2.05 ppm       doublet                                    NH.sub.3.sup.+      8.2 ppm                                                   CH.sub.2            3 and 4.15 ppm multiplet                                  ______________________________________                                    

EXAMPLE 5

3-(2'-isocamphyl-4',5'-dimethylphenoxy)-1-amino propan-2-ol

116g (0.45 mole) of 2-isocamphyl-4,5-dimethylphenol are dissolved in 700cm³ of toluene and 10.35g of sodium added. The mixture is refluxed untilcomplete dissolution of sodium occurs. After evaporation of the toluene,the phenate formed is dissolved in anhydrous tetrahydrofuran. 74 cm³(0.9 mole) of epichlorohydrin are added slowly to the solution which isrefluxed for 18 hours. The solvent is removed under reduced pressure,the residue is dissolved in ether, the ethereal solution is washedrapidly with water, dried over magnesium sulphate and the ether removed.The residue obtained is dissolved in a 1:1 mixture ofbenzene-cyclohexane and filtered on a silica column. There is thusobtained, as an oil, 137g of1-(2'-isocamphyl-4',5'-dimethylphenoxy)-2,3-epoxy propane. A solution of9.4g of the preceding product in 200 ml of ethanol containing 17g ofammonia is left for 3 days at ambient temperature. After evaporation,the residue is dissolved in ether, the ethereal solution is washed toneutrality and the ether removed under vacuum. The residue is taken upwith hydrochloric ether, the solvent evaporated and the residuecrystallised in propane. There is thus obtained 5g of pure product asthe hydrochloride (m.pt-260°-264° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.21 H.sub.34 NO.sub.2 Cl (M.W. = 367.9)                                C     H       N       O      Cl                                    ______________________________________                                        Calculated (%)                                                                             68.55   9.33    3.81  8.70  9.64                                 Found (%)    68.1    9.4     3.65        9.8                                  ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed.

    ______________________________________                                        Isocamphyl       2880, 2950 cm.sup.-1                                         Aromatic nycleus 1620, 1510, 850                                              Combined ether   1265, 1100                                                   NH.sub.3.sup.+   3000, 2660, 2000, 1600, 1510                                 >CH OH           OH: 3300 CO: 1080                                            ______________________________________                                    

N.M.R. SPECTRA

In deuterated chloroform, with a T.M.S. reference the following peaksare observed.

    ______________________________________                                        Isocamphyl:                                                                            CH.sub.3      0.8 ppm     doublet                                             CH.sub.3 geminal                                                                           1 ppm        Singlet                                             CH.sub.2 ethylamino                                                                        3.4 and 3.95 ppm                                                                           multiplets                                          NH.sub.3.sup.+                                                                             7.05 ppm                                                ______________________________________                                    

EXAMPLE 6

3-(2'-isocamphyl-4',5'-dimethylphenoxy)-1-isopropylamino propan-2-ol.

38g of 1-(2'-isocamphyl-4',5'-dimethylphenoxy)-2,3-epoxypropane,prepared as described in Example 5, and 100 cm³ of isopropylamine areplaced in contact for a week at ambient temperature. After removal ofexcess isopropylamine under reduced pressure, the residue is dissolvedin ether, the ethereal phase washed with water, dried over magnesiumsulphate, filtered and precipitated by addition of gaseous HCl. Bycrystallisation in acetone there is obtained 23g of the desired productin the form of the pure hydrochloride (m.pt = 172°-174° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.24 H.sub.40 NO.sub.2 Cl (M.W. = 410)                                  C      H        N        Cl                                        ______________________________________                                        Calculated (%)                                                                             70.3     9.76     3.42   8.06                                    Found (%)    70.1     9.6      3.4    7.85                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed:

    ______________________________________                                        Isocamphyl       2880 2950 cm.sup.-1                                          Aromatic nucleus 1620, 1590, 1510, 845                                        Combined ether   1265, 1110, 1040                                             NH.sub.2.sup.+ : 2800, 2540, 2410, 2000                                       >CH--OH          OH: 3350 CO: 1090                                            ______________________________________                                    

N.M.R. SPECTRA

In deuterated chloroform, with a T.M.S. reference, the following peaksare observed:

    ______________________________________                                        Isocamphyl    0.85 ppm        doublet                                         CH.sub.3 geminal                                                                            0.85 and 1.05 ppm                                                                             Singlets                                        CH.sub.3 (isopropyl)                                                                        1.45 ppm        doublet                                         CH.sub.2      3.3 and 4.05 ppm                                                                              multiplets                                      NH.sub.2.sup.+                                                                              7.7 ppm                                                         ______________________________________                                    

EXAMPLE 7

N-hydroxyethyl-2-(2'-isobornyl-4',5'-dimethylphenoxy) ethylamine.

In a flask fitted with a condenser and a nitrogen delivery tube, thereis introduced 0.5g of lithium aluminium hydride and 50 cm³ of anhydrousether. To the suspension, cooled to 0° C, there is added dropwise, withstirring, a solution of 3.6g (0.01 mole) ofN-hydroxyethyl-(2-isobornyl-4,5-dimethylphenoxy) acetamide in 250 cm³ ofanhydrous tetrahydrofuran. The mixture is warmed for 3 hours at 60° Cand then the excess hydride is destroyed, the mixture acidified, theorganic phase is separated and washed with water and dried overmagnesium sulphate. After evaporation of the solvent, the oily residueis crystallised in a 7:3 benzene/isopropyl ether mixture. There is thusobtained 2g of pure product as the hydrochloride (m.p - 158° C).

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.22 H.sub.36 NO.sub.2 Cl (M.W. = 381.97)                               C      H        N        Cl                                        ______________________________________                                        Calculated (%)                                                                             69.17    9.52     3.67   9.28                                    Found (%)    68.8     9.4      3.7    9.4                                     ______________________________________                                    

I.R. SPECTRA

In solution in chloroform, the following characteristic bands areobserved.

    ______________________________________                                        Isobornyl        2880, 2950 cm.sup.-1                                         Aromatic nucleus 1620, 1505, 850                                              Combined ether   1255, 1110, 1020                                             >NH.sub.2.sup.+  2750, 2500, 1590                                             --CH.sub.2 OH    OH: 3350 CO: 1050                                            ______________________________________                                    

N.M.R. SPECTRA

    ______________________________________                                        CH.sub.3                                                                              bridge head 0.65 ppm       Singlet                                    CH.sub.3                                                                              geminal     0.80 and 0.85 ppm                                                                            doublets                                   CH.sub.3                                                                              aromatic    2.15 ppm       Singlet                                    CH.sub.2            3.3 ppm        Massive                                    CH.sub.2            4 and 4.3 ppm  triplet                                    NH.sub.2.sup.+      9.3 ppm                                                   ______________________________________                                    

EXAMPLE 8 ##STR8## 1-Amino 3-(2'-isobornyl phenoxy) propan-2-ol

23g metallic sodium are added to a solution of 23g (0.1 mole)ortho-isobornyl-phenol. The mixture is refluxed in a nitrogen atmosphereuntil no further hydrogen is evolved, the solvent is removed underreduced pressure and the residue is taken up in 100 cm³ tetrahydrofuran.18.5g (0.2 mole) epichlorohydrin are added dropwise to the precedingsolution, then the mixture is refluxed for 18 hours. After evaporationof the solvent, it is taken up in ether, the ethereal phase is washed inwater, dried then the solvent is evaporated. 27g of a yellow/orange oil[1-(2'-isobornyl phenoxy) 2,3-epoxypropane] are obtained, which aredissolved in 400 cm³ methanol saturated with ammonia. After being leftfor 3 days at ambient temperature, the methanol is removed and theresidue is taken up in 500 cm³ hydrochloric ether. The precipitateformed is washed with ether, then crystallised in chlorobenzene. 8g ofpure product in the form of the hydrochloride are thus obtained. M.Pt. =240°-242° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for: C.sub.19 H.sub.30 O.sub.2 N Cl (M.W. 339.91)                               C      H        N        Cl                                        ______________________________________                                        Calculated % 67.14    8.90     4.12   10.43                                   Found %      67.22    8.95     4.20   10.53                                   ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr the following main bands are noted:

    ______________________________________                                        Isobornyl     2950, 2880 cm.sup.-1 ; 1475, 1455 cm.sup.-1                     --O--CH.sub.2 --                                                                            1245 cm.sup.-1                                                  OH            3360 cm.sup.-1                                                  ⊕ NH.sub.3                                                                              3000, 1990 cm.sup.-1                                            ______________________________________                                    

N.M.R. SPECTRA

In solution in D.M.S.O., the following peaks are observed with respectto H.M.D.S. as a reference:

    ______________________________________                                        Isobornyl  CH.sub.3                                                                              bridge head                                                                              0.60 ppm (s)                                               CH.sub.3                                                                              geminal    0.75 - 0.80 ppm (s)                             OH                            5.75 ppm                                        H aromatic                    7 ppm (multiplet)                               ⊕ NH.sub.3                8.25 ppm                                        --CH.sub.2 --                 3 - 3.95 ppm                                    (lateral chain)                                                               ______________________________________                                    

EXAMPLE 9 ##STR9## 1-Isopropylamino 3-(2'-isobornyl phenoxy) propan-2-ol

28.6g (0.1 mole) of 1-(2'-isobornyl phenoxy) 2,3-epoxypropane, preparedas in Example 8, are dissolved in 150 cm³ isopropylamine. After beingleft for 3 days at ambient temperature, the excess isopropylamine isremoved under vacuum and the residue is taken up in ether. The etherealphase is washed with water, dried over sodium sulphate and the solventis evaporated. The residue is taken up in a titrated solution ofhydrochloric ethanol. After evaporation, one crystallises from achloroform-ethanol mixture (5:5) and 24.6g of pure product in the formof the hydrochloride are obtained. M.Pt. 214°-216° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.32 H.sub.36 O.sub.2 N Cl (M.W. 382)                                   C      H        N        Cl                                        ______________________________________                                        Calculated % 69.18    9.50     3.66   9.28                                    Found %      69.10    9.63     3.80   9.15                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following characteristic bands are observed:

    ______________________________________                                        Isobornyl                                                                              2950, 2875 cm.sup.-1 ; 1455, 1475, 1370, 1380 cm.sup.-1              --0--CH.sub.2 --                                                                       1240, 1045 cm.sup.-1                                                 --⊕ NH.sub.2 --                                                                    2800 cm.sup.-1                                                       OH       3300 cm.sup.-1                                                       ______________________________________                                    

N.M.R. SPECTRA

In solution in D.M.S.O. the following peaks are observed with respect toH.M.D.S.:

    ______________________________________                                        Isobornyl                                                                             CH.sub.3                                                                              bridge head  0.68 ppm (s)                                             CH.sub.3                                                                              geminal      0.72 - 0.75 ppm (s)                              CH.sub.3        (Isopropyl)  1.2 ppm (doublet)                                CH.sub.2        (lateral chain)                                                                            3.1 - 3.9 ppm.                                   OH                           5.5 ppm                                          >NH.sub.2                    9 ppm                                            Aromatic                     6.95 ppm (multiplet)                             Protons                                                                       ______________________________________                                    

EXAMPLE 10 ##STR10## 2-(2-isobornyl-4-chloro-5-methyl phenoxy)ethylamine

13.9g (0.05 mole) of 2-isobornyl-4-chloro-5-methyl phenol, 150 cm³methylethyl ketone dried on CaCl₂ and 10.4g (0.075 mole) anhydrouspotassium carbonate are introduced into a 500 cm³ three necked flaskprovided with a condenser and supplied with a stream of nitrogen. Themixture is refluxed with stirring for 2 hours, there is then addeddropwise 75 cm³ of a normal solution of chloroacetonitrile inmethylethyl ketone containing potassium iodide. The latter is heatedunder reflux for 1 night, then the solvent is evaporated and the residuetaken up in cyclohexane at 60° C. After filtration on celite, thesolvent is evaporated and the residue crystallised in 25 cm³ heptane.13.4g of 2-isobornyl-4-chloro-5-methyl phenoxy acetonitrile are thusobtained.

A solution of 12.7g (0.04 mole) of the preceding product in 100 cm³tetrahydrofuran is subject for 1 hour to mixing with diborane carriedalong by a nitrogen current. The mixture is then left for 18 hours atambient temperature. After the addition of ethanol, it is concentratedat reduced pressure and treated with a solution of hydrochloric ether.The precipitate formed is crystallised in acetone. 6g of pure product inthe form of the hydrochloride are thus obtained. M.Pt. = 182°-184° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.19 H.sub.29 O N Cl.sub.2 (M.W. 358.35)                                C      H        N        Cl                                        ______________________________________                                        Calculated % 63.68    8.16     3.91   19.79                                   Found %      63.75    8.10     3.80   19.91                                   ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following main bands are noted:

    ______________________________________                                        --O-- CH.sub.2 --   1245 cm.sup.-1                                            ⊕ NH.sub.3      2900, 2020 cm.sup.-1                                      Isobornyl           2950, 2880 cm.sup.-1                                      Aromatic nucleus    1610, 1495 cm.sup.-1                                      ______________________________________                                    

N.M.R. SPECTRA

In solution in CDCl₃, the following peaks are noted with respect toT.M.S. reference:

    ______________________________________                                        Isobornyl  CH.sub.3                                                                             bridge head                                                                              0.62 ppm (s)                                                CH.sub.3                                                                             geminal    0.80 - 0.85 ppm (s)                              Aromatic nucleus                                                                         CH.sub.3          2.28 ppm (s)                                                       protons    6.65 - 7.22 ppm (s)                              CH.sub.2                     3.3 - 4.12 ppm                                   (lateral chain)                                                               ⊕ NH.sub.3               7.9 ppm                                          ______________________________________                                    

EXAMPLE ##STR11## 11 1-isopropylamino 3-(2'-isobornyl-4',5'-dimethylphenoxy) propan-2-ol

20g (0.064 mole) of 1-(2'-isobornyl-4',5'-dimethyl phenoxy)2,3-epoxypropane, prepared in Example 4, are dissolved in 40 cm³isopropylamine. After being left at ambient temperature for 7 days, theexcess isopropylamine is removed the residue is taken up in ether, theethereal phase is washed with water, dried and the ether is evaporated.The residual oil is dissolved in 100 cm³ ethanol. 24 cm³ of 3.4Nhydrochloric ethanol are added. One precipitates with ether andrecrystallises from an ethanol-chloroform mixture (97:3). 17g of pureproduct in the form of the hydrochloride are thus obtained. M.Pt. =218°-220° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.24 H.sub.40 O.sub.2 N Cl (M.W. 410.04)                                C      H        N        Cl                                        ______________________________________                                        Calculated % 70.30    9.83     3.42   8.65                                    Found %      70.20    9.72     3.53   8.57                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following main bands are noted:

    ______________________________________                                        Isobornyl        2950, 2880 cm.sup.-1                                         --O-- CH.sub.2   1260, 1110 cm.sup.-1                                         >⊕ NH.sub.2  2800, 2530 cm.sup.-1                                         OH               3350 cm.sup.-1                                               ______________________________________                                    

N.M.R. SPECTRA

In solution in CDCl₃, the following peaks are observed with respect tothe T.M.S. reference:

    ______________________________________                                        Isobornyl                                                                              CH.sub.3                                                                              bridge head                                                                              0.7 ppm (s)                                                CH.sub.3                                                                              geminal    0.8 - 0.9 ppm (doublet)                           Lateral Chain                                                                          CH.sub.3                                                                              (isopropyl)                                                                              1.5 ppm                                                    CH.sub.2           3.3 - 4 ppm                                                >⊕ NH.sub.2    7.2 ppm                                           Aromatic CH.sub.3           2.15 ppm (s)                                      Nucleus  H                  6.6 - 7.05 ppm (s)                                ______________________________________                                    

EXAMPLE 12 ##STR12## 1-amino 3 -(2'-isocamphyl-4'-methyl phenoxy)propan-2-ol 60g (0.245 mole) 2-isocamphyl-4-methyl phenol, 200 cm³anhydrous toluene and 5.63g (0.245 mole) sodium are introduced into athree-necked flask supplied with a current of nitrogen. The mixture isheated under reflux until no further hydrogen evolves, the solvent isremoved and the residue taken up in 200 cm³ anhydrous tetrahydrofuran.45.4g (0.49 mole) epichlorohydrin are added to the solution obtained,then the mixture is refluxed for 4 hours. After cooling, it is extractedwith ether, washed abundantly with water, dried and the ether isevaporated. 60g 1-(2'-isocamphyl-4'-methyl phenoxy) 2,3-epoxypropane areobtained in the form of an oil. 30g(0.1 mole) of this oil are dissolvedin 300 cm³ of a solution of ammonia in methanol and left in contact for1 night. The solvent is then evaporated and the residue taken up inhydrochloric ether. After cooling, 10g of product are obtained in theform of the hydrochloride, which is crystallised in methylethyl ketone.M.Pt. 235°-245° C (dec). ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.20 H.sub.32 O.sub.2 N Cl (M.W. 353.93)                                C      H        N        Cl                                        ______________________________________                                        Calculated % 67.87    9.11     3.96   10.02                                   Found %      67.73    9.18     4.05   10.11                                   ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following main bands are noted:

    ______________________________________                                        Isocamphyl  2960, 2880; 1480, 1465; 1380, 1370 cm.sup.-1                      --O-- CH.sub.2 --                                                                         1245, 1055 cm.sup.-1                                              Aromatic nucleus                                                               1600, 1510, 810 cm.sup.-1                                                    --⊕ NH.sub.3                                                                          2980, 1990 cm.sup.-1                                              OH          3380 cm.sup.-1                                                    ______________________________________                                    

N.M.R. SPECTRA

In solution in a D.M.S.O. - CDCl₃ mixture, the following peaks areobserved with respect to the T.M.S. reference:

    ______________________________________                                        Isocamphyl   CH.sub.3        0.90 ppm (d)                                                  CH.sub.3                                                                             geminal  0.90 - 1.05 ppm (s)                              CH.sub.2 lateral chain       3.15 - 4 ppm (m)                                 Aromatic protons             6.85 ppm (massive)                               --⊕ NH.sub.3             8 ppm                                            ______________________________________                                    

EXAMPLE 13 ##STR13## 1-isopropylamino 3-(2'-isocamphyl-4'-methylphenoxy) propan-2-ol

A solution of 30g (0.1 mole) of 1-(2'-isocamphyl-4'-methyl phenoxy)2,3-epoxypropane, (prepared in example 12) in 150 cm³ isopropylamine isleft at ambient temperature for 5 days. The excess amine is then removedand the residue is taken up in ether, the ethereal phase is washed inwater, dried and the ether is evaporated. The residue is dissolved inmethylethyl ketone. The precipitate formed by bubbling dry hydrochloricacid is re-crystallised from a mixture of methylethyl ketone andmethanol. 16g pure product in the form of the hydrochloride areobtained. M.Pt. = 208°-210° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.23 H.sub.38 O.sub.2 N Cl (M.W. 396.01)                                C      H        N        Cl                                        ______________________________________                                        Calculated % 69.76    9.67     3.54   8.95                                    Found %      69.68    9.82     3.40   9.10                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following bands are noted:

    ______________________________________                                        Isocamphyl       2960, 2870; 1475, 1460 cm.sup.-1                             --O-- CH.sub.2 --                                                                              1250, 1065 cm.sup.-1                                         NH.sub.2         2800 cm.sup.-1                                               OH               3350 cm.sup.-1                                               ______________________________________                                    

N.M.R. SPECTRA

In solution in a mixture of CDCl₃ - D.M.S.O. the following peaks areobserved with respect to the T.M.S. reference:

    ______________________________________                                        Isocamphyl                                                                              CH.sub.3              0.9 ppm (s)                                             CH.sub.3 geminal      0.9 - 1.02 ppm (s)                            Lateral Chain                                                                           --CH.sub.2 --         3.17 - 4 ppm (m)                                                 Isocamphyl (CH.sub.3)                                                                      1.45 ppm (d)                                                     OH           5.9 ppm                                                          >⊕ NH.sub.2                                                                            8.9 ppm                                       Aromatic                        6.85 ppm (m)                                  protons                                                                       ______________________________________                                    

EXAMPLE 14 ##STR14## EXAMPLE 14 1-isopropylamino b 3-[2'-(norbornyl)-4',5'-dimethyl phenoxy] propan-2-ol

108g (0.5 mole) of 2-norbornyl-4,5-dimethyl phenol, 600 cm³ anhydroustoluene and 11.5g (0.5 mole) sodium are introduced into a three-neckedflask supplied with a nitrogen stream. The reaction mixture is refluxedfor 4 hours, the solvent is then removed and the residue taken up in 500cm³ tetrahydrofuran. 39.4 cm³ (0.5 mole) epichlorohydrin are added andthe mixture is heated under reflux for 8 hours. One extracts with ether,washes the ethereal phase with water, dries and evaporates the solvent.123.6g of 1-(2'-norbornyl-4',5'-dimethyl phenoxy) 2,3-epoxypropane areobtained in the form of oil. 27.2g (0.1 mole) of the preceding productare dissolved in 100 cm³ isopropylamine. After 5 days contact, theexcess amine is evaporated under reduced pressure and extracted withether. After washing with water and drying, the ether is evaporated andthe residue taken up in chloroform. One precipitates by adding gaseoushydrochloric acid. By crystallisation in methylethyl ketone, 20g of pureproduct are obtained. M.Pt. 183°-185° C.

ANALYTICAL CHARACTERISTICS

    ______________________________________                                        Analysis for C.sub.21 H.sub.34 O.sub.2 N Cl (M.W. 367.96)                                C      H        N        Cl                                        ______________________________________                                        Calculated % 68.55    9.31     3.81   9.63                                    Found %      68.67    9.20     3.90   9.57                                    ______________________________________                                    

I.R. SPECTRA

In dispersion in KBr, the following main bands are noted:

    ______________________________________                                        Norbornyl     2950, 2870, 1470, 1460 cm.sup.-1                                --O-- CH.sub.2 --                                                                           1270, 1065 cm.sup.-1                                            >⊕ NH.sub.2                                                                             2800 cm.sup.-1                                                  OH            3420, 3320 cm.sup.-1                                            Aromatic nucleus                                                                            1620, 1590, 856 cm.sup.-1                                       ______________________________________                                    

N.M.R. SPECTRA

In solution in D.M.S.O., the following peaks are observed with respectto the H.M.D.S. reference:

    ______________________________________                                        Norbornyl                1.4 ppm (massive)                                    Aromatic nucleus                                                                         Protons       6.65 - 6.80 ppm (s)                                             CH.sub.3      2.1 ppm (s)                                          Lateral Chain                                                                            --O-- CH.sub.2 --                                                                           3.9 ppm (m)                                                     --CH.sub.2 -- 3.1 ppm                                                         OH            6.85 ppm                                                        NH.sub.2      9.05 ppm                                                        CH.sub.3 (isopropyl)                                                                        1.25 ppm (doublet)                                   ______________________________________                                    

BACTERIOSTATIC ACTIVITY

The new terpeno-phenoxyalkylamines according to the invention are usedparticularly as bacteriostatic agents in the treatment of infections byGram + and Gram bacteria.

The bacteriostatic activity of the products according to the inventionhave been evaluated by the method of streaks in gelose media. Thismethod comprises making increasing dilutions of the product to betested, in nutritive gels poured in a Petri dish.

The bacteria to be studied are introduced onto the geloses in parallelstreaks by means of a platinum loop which has been immersed in a 24 hourold culture of the bacteria.

The bacteriostatic amount corresponds to the weakest concentration forwhich the bacteria does not develop along the length of the striations.

The activity of the compounds has been studied vis a vis gram + ve(Staphylococcus aureus) and gram - ve (Escherichia coli) bacteria.

The table below shows the minimum inhibitory concentrations, expressedin mg/1 of the products of the examples.

    ______________________________________                                                     Minimum inhibitory concentration                                              (mg/liter)                                                                    Staphylococcus                                                                           Escherichia                                                        aureus     coli                                                  ______________________________________                                        Product of Example                                                                         1     5            7.5                                                        2     5            10                                                         3     7.5          5                                                          4     5            5                                                          5     5            5                                                          6     5                                                                       7     10           30                                                         8     20           7.5                                                        10    7.5          7.5                                                        12    7.5          5                                             ______________________________________                                    

CORONARO-DILATORY EFFECTS

They were measured in vitro on a heart taken from a rabbit, according toLangendorff's technique. The terpenophenoxy alkylamines according to theinvention are administered to the aortic canal at a constant volume of 1cm³ for 1 minute.

The following table indicates the increase in the coronary output andthe duration of this variation, depending on the doses.

    ______________________________________                                        Product                                                                       of     DOSE     Coronary output                                               Example                                                                              μg/cm.sup.3                                                                         Variations in %                                                                             Duration in mins.                               ______________________________________                                        1      3        + 37          5                                                      10       + 55          5                                               2      1        + 23          >15                                                    3        + 39          >15                                             3      1        + 4           3                                                      3        + 36          >15                                             4      3        +127          15                                                     10       +140          12                                              5      1        + 13          2                                                      3        + 70          >15                                             6      3        + 36          15                                                     10       + 66          9                                               7      3        + 51          >15                                                    10       +109          >15                                             8      3        + 24          6                                                      10       + 63          12                                              9      3        + 95          4                                                      10       +102          4                                               10     1        + 34          >15                                                    3        + 60          >15                                             11     3        + 72          5                                                      10       +210          12                                              12     100      + 31          4                                               ______________________________________                                    

The terpeno-phenoxyalkylamines according to the invention may be used asvaso-dilatory or cardio-vascular anti-infectious agents. To this end,they may be made in an appropriate form for administration orally, forexample tablets capsules etc. containing 50 mg - 200 mg of activeingredient and the dose to be administered is 100 mg to 1000 mg ofactive ingredient per day.

What is claimed is:
 1. A terpeno-phenoxyalkylamine of the generalformula: ##STR15## in which n is 0, 1 or 2, R₁ is a hydrogen atom, alower alkyl radical having a straight or branched chain with 1 to 4carbon atoms, or an OH group,R₂ and R₃ each represent H, or a loweralkyl radical having a straight chain or branched chain with up to 4carbon atoms, or a hydroxyethyl radical, R₄ is a terpene radical chosenfrom the following group: ##STR16## of exo or endo configuration, in theortho, meta or para position with respect to the ether function, R₅ andR₆ may each be H, a lower alkyl radical having a straight or branchedchain with up to 4 carbon atoms or a halogen atom, or a physiologicallyacceptable non-toxic acid salt or quaternary ammonium salt thereof.
 2. Aterpeno-phenoxyalkylamine according to claim 1, characterised in that:R₁is H or OH n is equal to zero or 1 R₂ is a hydrogen atom, R₃ is ahydrogen atom or an isopropyl radical, or a hydroxyethyl group (- CH₂CH₂ -OH) R₅, r₆ each represent a hydrogen atom or a halogen atom, or amethyl radical in position 4 or 5 of the phenol ring. 3.2-(2'-isobornyl-4',5'-dimethyl phenoxy) ethylamine in the form of a baseof a physiologically acceptable non-toxic acid salt, or quaternaryammonium salt thereof.
 4. 2-(2'-isobornyl-4'-bromo-5'-methyl phenoxy)ethylamine in the form of a base or a physiologically acceptablenon-toxic acid salt or quaternary ammonium salt thereof. 5.2-(2'-isobornyl-4'-bromo phenoxy) ethylamine in the form of a base or aphysiologically acceptable non-toxic acid salt or quaternary ammoniumsalt thereof.
 6. 3-(2'-isobornyl-4',5'-dimethyl phenoxy) 1-aminopropan-2-ol in the form of a base or a physiologically acceptablenon-toxic acid salt or quaternary ammonium salt thereof. 7.3-(2'-isocamphyl-4',5'-dimethyl phenoxy) 1-amino propan 2-ol in the formof a base or a physiologically acceptable non-toxic acid salt orquaternary ammonium salt thereof.
 8. 3-(2'-isocamphyl-4',5'-dimethylphenoxy) 1-isopropylamino propan 2-ol in the form of a base or aphysiologically acceptable non-toxic acid salt or quaternary ammoniumsalt thereof.
 9. N-hydroxyethyl 2-(2'-isobornyl-4',5'-dimethyl phenoxy)ethylamine in the form of a base or a physiologically acceptablenon-toxic acid salt or quaternary ammonium salt thereof.
 10. 1-amino3-(2'-isobornyl phenoxy) propan-2-ol in the form of a base of aphysiologically acceptable non-toxic acid salt or quaternary ammoniumsalt thereof.
 11. 1-isopropyl amino 3-(2'-isobornyl phenoxy)propan-2-olin the form of a base of a physiologically acceptablenon-toxic acid salt or quaternary ammonium salt thereof. 12.2-(2-isobornyl-4-chloro-5-methyl phenoxy) ethylamine in the form of abase or a physiologically acceptable non-toxic acid salt or quaternaryammonium salt thereof.
 13. 1-isopropylamino 3-(2'-isobornyl-4',5'dimethyl phenoxy propan-2-ol in the form of a base or a physiologicallyacceptable non-toxic acid salt or quaternary ammonium salt thereof. 14.1-Amino 3-(2-isocamphyl-4'-methyl phenoxy) propan-2-ol in the form of abase or a physiologically acceptable non-toxic acid salt or quaternaryammonium salt thereof.
 15. 1-isopropylamino 3-(2'-isocamphyl-4'-methylphenoxy) propan-2-ol in the form of a base or a physiologicallyacceptable non-toxic acid salt or quaternary ammonium salt thereof. 16.1-isopropylamino 3-[2'-norbornyl-4',5'-dimethyl phenoxy] propan-2-ol inthe form of a base or a physiologically acceptable non-toxic acid saltor quaternary ammonium salt thereof.
 17. A pharmaceutical compositionuseful for causing vaso-dilatation of the coronaries in a patientcontaining as the active agent a terpeno-phenoxyalkylamine according toclaim 1 in a physiologically active amount and a non-toxicpharmaceutically acceptable carrier.
 18. A method for causingvaso-dilation of the coronaries in a patient consisting of administeringorally to said patient a pharmaceutical composition according to claim17 in a dose providing 100 to 1000 mg of active ingredients per day.